Crosstalk Between Activated Myofibroblasts and β Cells in Injured Mouse Pancreas

Bayan, Jennifer–Ann; Peng, Zhechu; Zeng, Ni; He, Liyun; Chen, Jingyu; Stiles, Bangyan L.

doi:10.1097/mpa.0000000000000431

Cited by 8 publications

(9 citation statements)

References 28 publications

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“…For example, in addition to infiltrating macrophages stimulated by HO-1 induction, Husseini and colleagues also identified infiltrating CD34+ cells that resembled mesenchymal cells (vimentin+), fibroblasts (α-SMA+), and fibrocytes (collagen V+) [61]. These findings were consistent with previous studies suggesting that ECM components [70,71] and mesenchymal stem cells [72] recruit polarized, proliferative macrophages in response to tissue damage. Complex remodeling of ECM [73] by macrophages in concert with other cell types is an understudied area of β-cell regeneration research and undoubtedly warrants future attention.…”

Section: Introductionsupporting

confidence: 80%

Replicative capacity of β-cells and type 1 diabetes

Saunders

Powers

2016

Journal of Autoimmunity

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Efforts to restore β-cell number or mass in type 1 diabetes (T1D) must combine an intervention to stimulate proliferation of remaining β-cells and an intervention to mitigate or control the β-cell-directed autoimmunity. This review highlights features of the β-cell, including it being part of a pancreatic islet, a mini-organ that is highly vascularized and highly innervated, and efforts to promote β-cell proliferation. In addition, the β-cell in T1D exists in a microenvironment with interactions and input from other islet cell types, extracellular matrix, vascular endothelial cells, neuronal projections, and immune cells, all of which likely influence the β-cell’s capacity for replication. Physiologic β-cell proliferation occurs in human and rodents in the neonatal period and early in life, after which there is an age-dependent decline in β-cell proliferation, and also as part of the β-cell’s compensatory response to the metabolic challenges of pregnancy and insulin resistance. This review reviews the molecular pathways involved in this β-cell proliferation and highlights recent work in two areas: 1) Investigators, using high-throughput screening to discover small molecules that promote human β-cell proliferation, are now focusing on the dual-specificity tyrosine-regulated kinase-1a and cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p21 as targets of compounds to stimulate adult human β-cell proliferation. 2) Local inflammation, macrophages, and the local β-cell microenvironment promote β-cell proliferation. Future efforts to harness the responsible mechanisms may lead to new approaches to promote β-cell proliferation in T1D.

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Section: Introductionsupporting

confidence: 80%

Replicative capacity of β-cells and type 1 diabetes

Saunders

Powers

2016

Journal of Autoimmunity

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“…Whether the mice were fasting or fed, plasma glucose also did not differ significantly between the two strains of mice (68.5 Ϯ 9.6 versus 61 Ϯ 3.8 mg/dl). Subcutaneous (s.c.) injections of tamoxifen (Sigma-Aldrich, St. Louis, MO), every other day for a total of 5 injections, were used to induce ␤-cell-specific deletion of Akt1 (␤A1KO) (68,69). The efficiency of this injection protocol is assessed with yellow fluorescent protein (YFP) expression, AKT1 protein levels, and phosphorylation of its substrate, pPRAS40, in ␤A1KO mouse islets (Fig.…”

Section: Methodsmentioning

confidence: 99%

AKT1 Regulates Endoplasmic Reticulum Stress and Mediates the Adaptive Response of Pancreatic β Cells

Peng

Aggarwal

Zeng

et al. 2020

Molecular and Cellular Biology

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Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin-regulated glucose metabolism, while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic β cells. Using a mouse model with inducible β-cell-specific deletion of the Akt1 gene (βA1KO mice), we showed that AKT1 is involved in high-fat-diet (HFD)-induced growth and survival of β cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, βA1KO mice presented the same metabolic profile and β-cell phenotype as the control mice with an intact Akt1 gene. When metabolic stress was induced by HFD, β cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in βA1KO mice. We further demonstrated that AKT1 protein deficiency caused endoplasmic reticulum (ER) stress and potentiated β cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to the induction of eukaryotic initiation factor 2 α subunit (eIF2α) signaling and ER stress markers under normal-chow-fed conditions, indicating chronic low-level ER stress. Together, these data established a role for AKT1 as a growth and survival factor for adaptive β-cell response and suggest that ER stress induction is responsible for this effect of AKT1.

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“…This enhanced metabolic phenotype however is paradoxical with the enhanced metabolic functions associated with PTEN loss observed with the tissue specific Pten deletion mice. In adipose tissue, liver, pancreatic β-cells and muscle, deletion of Pten consistently lead to enhanced insulin and metabolic sensitivity as well as resistance to HFD induced diabetes ( 88 , 89 , 107 , 129 – 131 ). In addition to the enhanced ability to transport and metabolize glucose by adipocytes, myocytes and hepatocytes, PTEN loss was associated with enhanced energy expenditure in brown adipose tissue ( 128 ).…”

Section: Paradoxical Roles Of Pten Regulated Metabolic and Growth Sigmentioning

confidence: 99%

PTEN: Tumor Suppressor and Metabolic Regulator

et al. 2018

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Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP3), PTEN reduces the level of PIP3, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment.

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Crosstalk Between Activated Myofibroblasts and β Cells in Injured Mouse Pancreas

Cited by 8 publications

References 28 publications

Replicative capacity of β-cells and type 1 diabetes

Replicative capacity of β-cells and type 1 diabetes

AKT1 Regulates Endoplasmic Reticulum Stress and Mediates the Adaptive Response of Pancreatic β Cells

PTEN: Tumor Suppressor and Metabolic Regulator

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